In 2019, the American Society for Transplantation and Cellular Therapy (ASTCT) developed consensus definitions and grading criteria for the common immune effector cell (IEC)-associated toxicities of cytokine release syndrome (CRS) and IEC-associated neurotoxicity syndrome (ICANS). These grading scales were widely adopted by clinicians, investigators, and sponsors, allowing a clearer understanding of outcomes across clinical trials and a uniform basis to inform treatment algorithms. Since then, other IEC class effects, such as IEC-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) and non-ICANS attributable neurotoxicity, have been recognized. ASTCT convened experts for 2 tasks. First, to consider updating the previously published ASTCT grading criteria for CRS, ICANS, and IEC-HS. Second, to consider existing definitions and grading criteria, and/or create consensus criteria for emerging toxicities, including immune effector cell-associated hematotoxicity; non-ICANS neurological toxicities such as parkinsonism, cranial nerve palsies, and polyneuropathies; IEC-associated enterocolitis; tumor inflammation-associated neurotoxicity; and on-target, off-tumor toxicities. These updated consensus toxicity definitions and grading criteria can facilitate comparisons of toxicities of IEC and T-cell engager therapy across clinical trials and in real-world settings, as well as aid clinicians in better characterizing the severity of toxicity that can ultimately be tied to management guidelines.
Although recent studies suggested an enhanced graft-versus-tumor (GVT) effect with cord blood transplantation (CBT), higher rates of engraftment failure, acute graft-versus-host disease (GVHD), and infections, including cytomegalovirus (CMV), contribute to increased nonrelapse mortality (NRM). Thus, further optimization of GVHD and infection prophylaxis strategies for CBT is warranted. This study evaluated the impact of GVHD prophylaxis with methotrexate (MTX) versus mycophenolate mofetil (MMF) after CBT on CMV infection and survival outcomes, considering the use of letermovir (LTV) prophylaxis. We studied 2849 CMV seropositive adult patients who underwent CBT. In the absence of LTV, 6-month csCMVi was significantly higher in patients receiving MTX than in those receiving MMF (64.7% vs. 52.1%, P < 0.001), while a similar incidence of csCMVi was observed with LTV (28.2% vs. 32.9%, P = 0.098). Multivariable analyses confirmed these findings. The risk of acute GVHD was lower in patients receiving MTX than in those receiving MMF, regardless of LTV use. NRM at 12 months was comparable between patients receiving MTX and MMF without LTV (19.1% vs. 20.4%, P = 0.577). Importantly, LTV mitigated the disadvantage of MTX with respect to csCMVi, and patients receiving MTX with LTV exhibited a lower NRM than those receiving MMF with LTV (11.5% vs. 17.8%, P = 0.003), a finding that remained significant in multivariable analysis. This study highlights the potential for further optimization of GVHD and infectious prophylaxis strategies in CBT, thereby reducing NRM while maintaining a potent GVT effect.
BACKGROUND:Cryopreservation of hematopoietic stem cell grafts has become more widely adopted. The impact of cryopreservation on clinical outcomes remains ambiguous with existing studies limited by retrospective designs, and heterogeneity in transplant protocol. The implications of cryopreservation of grafts on donor chimerism is also not well researched. METHODS:We retrospectively analysed 154 adults undergoing unrelated donor allogeneic HCT with reduced-intensity conditioning and ATG-based GVHD prophylaxis. Patients received either cryopreserved (n=85) or fresh (n=69) peripheral blood stem cell grafts. Day +60 chimerism was performed in 83.5% (n=71) patients in the cryopreserved arm and 82.6% (n=57) patients in the non-cryopreserved arm). Primary endpoint was day +60 lineage-specific donor chimerism comparison between the two groups. Secondary endpoints included comparison of engraftment kinetics, GVHD, relapse, overall survival (OS), progression-free survival (PFS), and graft-versus-host disease-free relapse-free survival (GRFS). RESULTS:Cryopreserved grafts were associated with lower median day +60 CD3+ donor chimerism (89% vs 95.5%; p=0.03) while CD33+ chimerism was unaffected. Neutrophil (Median 18 vs 16 days; P<0.01) and platelet (Median 19 vs 17 days; P<0.01) engraftment were modestly delayed, and hospital stay was longer (Median 36 vs 31 days; P=0.01) for cryopreserved grafts. Rates of acute and chronic GVHD, relapse and non-relapse mortality were not different between the two groups. Survival outcomes, namely OS, PFS, and GRFS were also similar between groups. Multivariate analysis showed cryopreservation of stem cells was independently associated (OR - 2.39; 95% CI 1.08-5.30) with reduced likelihood of D+60 full (>95% on both lineages) donor chimerism (33.8% vs 54.4%; p=0.03). CONCLUSIONS:Cryopreservation was associated with modestly lower early donor CD3+ chimerism and delayed engraftment but did not appear to affect relapse or survival in unrelated donor HCT with reduced-intensity conditioning and ATG-based GVHD prophylaxis. While larger studies looking specifically at impact of cryopreservation on donor chimerism are needed, our data supports the safe use of cryopreserved grafts in this setting.
INTRODUCTION:As survival after hematopoietic cell transplantation (HCT) improves, employment has emerged as a key survivorship outcome. However, little is known about employment attainment and sustainability among adolescent and young adult (AYA) survivors without prior work experience. METHODS:We conducted a nationwide cross-sectional survey of HCT survivors transplanted at ≤39 years of age, aged ≥20 years at survey, and without continuous employment before diagnosis. We evaluated employment attainment, timing of first employment, and subsequent outcomes, including leave of absence and resignation. Cumulative incidence was estimated using the Kaplan-Meier method, and associated factors were analyzed using Cox regression models. RESULTS:Among 240 participants, 186 (78%) achieved employment after HCT. The cumulative incidence of employment reached 49% and 60% at 5 and 10 years, respectively. Median age at first employment was 22 years (range, 16-45), with all but one entering the workforce by their 20s. Among employed participants, 16% experienced leave of absence and 37% resigned, both occurring at a median of 2 years. Female sex and the presence of occupational healthcare staff were associated with higher incidence of leave, whereas occupational healthcare staff was associated with lower risk of resignation. Employment trajectories were dynamic with frequent transitions in status and type. CONCLUSION:Although most AYA HCT survivors without prior work experience successfully entered the workforce, maintaining stable employment remained challenging. Employment attainment and employment sustainability appear to represent distinct survivorship outcomes, highlighting the need for longitudinal multidisciplinary support addressing both medical and developmental factors.
BACKGROUND:Children with sickle cell disease (SCD) increasingly undergo HLA-identical sibling donor hematopoietic cell transplant (HCT), yet the optimal conditioning intensity remains uncertain. Myeloablative conditioning (MAC) has been the conventional approach, but reduced-intensity conditioning (RIC) and nonmyeloablative conditioning (NMA) may achieve cure with less toxicity. OBJECTIVE:Among pediatric patients with SCD undergoing HLA-identical HCT, to compare outcomes by conditioning intensity. STUDY DESIGN:We evaluated all patients who underwent HLA-identical HCT for SCD at a single pediatric center from 2012-2025. Data were retrospectively collected for MAC and RIC recipients and prospectively collected for NMA recipients enrolled on two clinical trials (NCT03587272, NCT06358638). RESULTS:Among 91 patients studied, 50 received busulfan-based MAC, 10 received alemtuzumab/fludarabine/melphalan ± thiotepa RIC, and 31 received alemtuzumab/300 cGy total body total body irradiation (TBI) ± daratumumab NMA. Compared with MAC and RIC, NMA recipients required significantly less supportive care, including markedly less use of patient-controlled analgesia, total parenteral nutrition, transfusions, and hospitalization. No NMA recipients developed the combined graft-versus-host disease (GVHD) endpoint (acute grade 2-4 or chronic GVHD), compared with 20% of MAC and 30% of RIC recipients. Graft failure occurred in only one patient (NMA), although eight patients (4 RIC and 4 NMA) underwent successful low-toxicity second HCT for declining donor myeloid chimerism to avert secondary graft failure. All four deaths occurred in the MAC group (8%). The proportion of patients alive without SCD at last follow-up in each group was: MAC 46/50 (92%), RIC 10/10 (100%), NMA 30/31 (96.8%). Post-HCT cardiac and pulmonary function were similar across groups, while ovarian reserve measured by anti-Müllerian hormone was significantly higher after NMA. CONCLUSION:NMA conditioning with alemtuzumab and low-dose TBI substantially reduces toxicity compared with MAC and RIC. Although some patients require second HCT to improve donor engraftment, overall outcomes support this NMA approach as an option for children and adolescents with SCD.
Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for B-cell acute lymphoblastic leukemia (B-cell ALL). An important mechanism for the prevention of relapse is the graft-versus-leukemia (GVL) effect, potentially at the expense of the accompanying graft-versus-host disease (GVHD), which has varying morbidity and mortality depending on its timing and grade. The association between the development of acute GVHD and chronic GVHD and a reduced incidence of relapse in B-cell ALL has been documented extensively, although conflicting results have been described in certain settings, including haploidentical HSCT followed by post-transplant cyclophosphamide (PTCy). We retrospectively examined the transplant-related outcomes of B-cell ALL adult patients undergoing HLA-matched related donor HSCT or haploidentical HSCT plus PTCy in a single center, and its association with acute and chronic GVHD. We included 43 patients with a median age of 22 years, of whom 65.1% were male. The graft source was peripheral blood stem cells in all cases. The donor source was HLA-matched related in 30.2% of cases, and haploidentical in 69.8%. Moreover, the conditioning regimen was myeloablative in 30.2% and reduced-intensity in 69.8%. Most patients underwent HSCT in first or second complete remission (44.2% each). Measurable residual disease was positive in 11.6% of patients prior to HSCT. The 2-year cumulative incidence of relapse, non-relapse mortality and overall survival (OS) were 33.3%, 7.4% and 65.5%, respectively. In a multivariable Cox-regression analysis, we found no association between acute GVHD (HR 0.94, 95% CI 0.28-3.15, p = 0.92), mild chronic GVHD (HR 0.56, 95% CI 0.06-5.23, p = 0.61) or moderate-severe chronic GVHD (HR 0.49, 95% CI 0.04-4.86, p = 0.54) and the occurrence of relapse. Also, there was no association between acute or chronic GVHD of any grade and OS. A positive MRD status showed an association with the incidence of relapse (HR 2.32, 95% CI, 0.55-9.77, p = 0.24) and OS (HR 2.17, 95% CI, 0.55-8.51, p = 0.26). In conclusion, acute and chronic GVHD were not related to differences in relapse or survival after allogeneic HSCT followed by PTCy-based GVHD prophylaxis. This underscores the importance of reappraising the role of GVHD and GVL in evolving transplant settings.
BACKGROUND:Acute graft-versus-host disease (aGvHD) remains a major complication after allogeneic hematopoietic cell transplantation (alloHCT). Adoptive regulatory T-cell (Treg) therapy may suppress alloreactive T-cell responses, but clinical implementation has been limited by donor-specific manufacturing, prolonged ex vivo expansion, and logistical complexity. OBJECTIVE:We developed ATreg, a cell therapy product consisting of gp120-activated, polyclonal Tregs derived from HLA-unmatched third-party donors. The primary objective was to assess the safety, tolerability and toxicity of ATreg, hypothesizing that this would be feasable and safe for aGvHD prevention early after alloHCT in patients with hematologic malignancies. STUDY DESIGN:ATreg-001 is a first-in-human, prospective, open-label, single-arm, multi-center phase 1/2 trial (EU CT number 2024-516599-14-00) conducted at four German centers (Mainz, Dresden, Münster, Dortmund). ATreg was generated from standard non-mobilized apheresis products by Treg isolation followed by 16 hours of gp120-mediated activation in the presence of IL-2, without ex vivo expansion, thereby enhancing suppressive function and (potentially) enabling a therapeutic effect at substantially lower Treg doses. Ten patients received ATreg at 0.1-1.0 × 10⁶ cells/kg body weight on day +10 ± 5 after alloHCT, in addition to standard GvHD prophylaxis, in a dose-escalation design across three cohorts. ATreg was administered within 24 hours after manufacturing. The primary endpoint was the type, incidence, and severity of ATreg-related serious adverse events within 14 days after administration. Secondary endpoints included manufacturing feasibility, aGvHD incidence/severity within 100 days, engraftment, and infections. RESULTS:ATreg administration was well tolerated, with no infusion-related toxicities or other safety signals attributable to ATreg. All treated patients achieved hematopoietic engraftment and full donor chimerism. Within 100 days after alloHCT, no grade 3-4 aGvHD occurred, the cumulative incidence of grade 2-4 aGvHD was 10%, and no non-relapse mortality was observed. CONCLUSION:These first clinical data support the feasibility and favorable safety profile of ATreg, a third-party, gp120-activated Treg product requiring no ex vivo expansion, and warrant further evaluation in larger prospective clinical trials. MAIN POINTS:
This Correspondence responds to Oh and colleagues' study on nosocomial respiratory virus infections in hematologic malignancies and risk factors for progression to lower respiratory tract infection. We raise three methodological concerns: (1) the landmark analysis used to evaluate URTI-stage ribavirin therapy excludes patients who progressed or died before landmark time points, introducing selection bias by conditioning on a collider; (2) antiviral therapy analyses are severely underpowered (only 15 PIV and 9 RSV treated patients), with wide confidence intervals precluding definitive conclusions and substantial Type II error risk; and (3) combining glucocorticoid exposures from different indications (short-course pulse vs. prolonged therapy) may mask heterogeneous effects on immune function and viral progression. We commend the authors' risk stratification framework while urging cautious interpretation of antiviral efficacy data and recommending future prospective studies with adequate sample sizes and refined corticosteroid characterization.
BACKGROUND:Mismatched donor platforms have expanded access to allogeneic blood and bone marrow transplantation (alloBMT), providing patients near universal access often with multiple viable donor options. Thus, identifying optimal donors has become increasingly important. Existing observational studies on the subject assess outcomes only among patients who successfully proceeded to alloBMT, leaving earlier, donor-related barriers, logistical challenges, and costs unexamined. OBJECTIVES:The primary objective was to evaluate and compare donor-related transplants logistics by donor types, including frequency, cause, and duration of donor-related delays and cancellations. STUDY DESIGN:We conducted a retrospective analysis of patients with hematologic malignancies who underwent alloBMT with post-transplant cyclophosphamide (PTCy) at a single institution. We evaluated overall survival (OS) in all patients between 2018 and 2025 by donor type. We then assessed donor-related transplant delays or cancellations, as well as total transplant and graft charges by donor type in 374 consecutive patients transplanted between January 1, 2024, and December 31, 2025. RESULTS:In 1298 patients, OS did not differ by donor-type. Compared to related donors (RDs), unrelated donor (URD) transplants in 2024-2025 were more likely to experience a donor-related delay (26% vs 2.2 %, p<0.001). Both URDs (OR 15.1, 95% CI 6.42 - 41.7; p <0.001) and Black patients (OR 2.98, 95% CI 1.27-6.66; p = 0.010) had significantly increased odds of donor-related delays on univariable regression. Charges for URD transplants were significantly higher than RD ($184,036 vs $150,716 p <0.001), driven by graft acquisition charges. CONCLUSIONS:Using PTCy, survival outcomes were comparable across donor types. Related donors were more likely to advance to a timely donation, highlighting the need for further studies and interventions into donor and logistical barriers which could delay URD alloBMT.
BACKGROUND:Peripheral neuropathy (PN) is an uncommon but clinically significant complication after allogeneic hematopoietic stem cell transplantation (HSCT). However, the incidence, clinical features, risk factors, and electrophysiological characteristics of PN remain unclear. OBJECTIVE:To determine the incidence and risk factors of post-transplant PN (PTPN) and characterize its electrophysiological features using nerve conduction studies (NCS). STUDY DESIGN:We retrospectively analyzed consecutive patients aged ≥ 16 years who underwent first allogeneic HSCT at the Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital between January 2010 and December 2022. The primary endpoint was cumulative PTPN incidence. The cumulative incidence of PTPN was estimated with death treated as a competing event. Overall survival (OS) after PTPN onset was estimated using the Kaplan-Meier method. Risk factors for PTPN were evaluated using univariate and multivariate analyses using the Fine-Gray hazard model. Acute and chronic graft-versus-host disease (GVHD) were analyzed as time-dependent covariates. NCS findings were reviewed to characterize electrophysiological features and identify factors associated with reduced conduction parameters. RESULTS:Among 1,332 patients who underwent HSCT, 57 developed PTPN. The 3-year cumulative incidence was 3.9% (95% confidence interval [CI], 2.9-5.1). Median time from HSCT to PTPN onset was 195 days (range, 11-1,917). At PTPN onset, motor weakness and sensory disturbances were observed in 51 (89.5%) and 53 (93.0%) patients, respectively. Among 20 patients treated with intravenous immunoglobulin and/or methylprednisolone pulse therapy, only 2 (10.0%) showed symptomatic improvement. Multivariable analysis identified re-transplantation (hazard ratio [HR], 1.87; 95% CI, 1.05-3.34), grade II-IV acute GVHD (HR, 2.32; 95% CI, 1.34-4.00), and extensive chronic GVHD (HR, 4.27; 95% CI, 2.18-8.36) as independent risk factors for PTPN. Median survival after PTPN onset was 218 days (range, 5-3,106), and the 3-year overall survival rate after PTPN onset was 33.0% (95% CI, 20.9-45.6). NCS was performed in 55 patients and 53 (96.4%) showed axonal-type neuropathy. Motor and sensory amplitudes were generally lower in the lower extremities than in the upper extremities. Median ulnar motor nerve conduction velocity and compound muscle action potential amplitude were 47.7 m/s and 3.4 mV, respectively, whereas the corresponding tibial values were 37.6 m/s and 2.2 mV. Median ulnar sensory nerve conduction velocity and sensory nerve action potential amplitude were 48.4 m/s and 12.2 μV, respectively, whereas the corresponding sural values were 42.7 m/s and 4.2 μV. Older age (≥ 50 years), male sex, re-transplantation, and PTPN onset within 200 days after HSCT were associated with reduced nerve conduction velocities or amplitudes. CONCLUSION(S):PTPN was associated with GVHD and re-transplantation and was characterized predominantly by axonal neuropathy. The electrophysiological pattern suggests that PTPN may represent a distinct neurological complication rather than classical immune-mediated demyelinating neuropathy. Further studies are needed to clarify its pathophysiology and develop transplant-specific diagnostic and treatment strategies.
Acute graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, although the diverse roles of neutrophils in inflammation and cancer have been recognized, the specific contributions of distinct neutrophil subsets to acute GVHD remain unclear. Herein, we performed a prospective clinical study to investigate the role of distinct neutrophil subsets in G-CSF-mobilized peripheral blood (PB) graft on acute GVHD and to establish statistical prediction models. Our study demonstrated that the early committed neutrophil progenitor (proNeu1) was a risk factor, whereas immature neutrophil (immatureNeu) was a protective factor for grade Ⅱ-Ⅳ acute GVHD. The prediction model based on donor age, proNeu1 and immatureNeu showed significant accuracy for Ⅱ-Ⅳ acute GVHD diagnosis, with an area under the curve (AUC) of 0.782 (95% CI, 0.67-0.88) for the training set and an AUC of 0.771 (95% CI, 0.63-0.91) for the validation set. In addition, Decision Curve Analysis (DCA) indicated that the prediction model possessed high clinical utility. High risk group based on the prediction model is correlated with higher 100-day cumulative incidence of acute GVHD and 1-year cumulative incidence of chronic GVHD. The prediction model based on proNeu1 and immatureNeu subsets provides a risk assessment tool for clinicians to better predict and manage the course of acute GVHD. Moreover, we demonstrated that donor-derived CD10-immature neutrophils in the G-CSF-mobilized PB grafts as an immunoregulatory neutrophil were associated with attenuated acute GVHD, potentially through increased Reactive Oxygen Species (ROS) levels.
Chronic graft-versus-host disease (cGVHD) causes morbidity and mortality in pediatric patients following allogenic hematopoietic stem cell transplantation. Standard first-line therapy with corticosteroids is often insufficient, causes significant side effects and many children require multiple other lines of systemic therapy. Belumosudil, an oral ROCK2 inhibitor, has demonstrated immunomodulatory and antifibrotic effects and is FDA-approved for cGVHD if ≥12 years after failure of at least two prior systemic therapies. Data in pediatrics remains limited. We conducted a single-institution retrospective analysis of pediatric patients with steroid resistant/progressive cGVHD at Rady Children's Hospital of Orange County treated with belumosudil between September 2021 and July 2025. Eleven patients were identified. Longitudinal responses across organ systems with NIH consensus scoring, steroid dose reductions, pulmonary function testing (PFT), laboratory parameters, lung scans and qualitative symptoms assessments were collected. Of 11 patients treated with belumosudil, 10 demonstrated partial response and one a complete response. Corticosteroid and other immunosuppressant use decreased in 9 patients. PFTs were stable with improved clinical pulmonary symptoms. Qualitative improvements were decreases in rash, gastrointestinal upset and dry eyes. Safety was acceptable, with no peripheral blood count suppression or serious infections. Good compliance was observed with no discontinuation due to side effects. Belumosudil demonstrates promising efficacy in treating pediatric cGVHD by offering clinically meaningful responses with an acceptable safety profile. Its corticosteroid-sparing potential and impact on quality of life further support its role in the management of cGVHD. Continued investigation in younger children and in earlier lines of therapy is warranted to optimize outcomes in this vulnerable population.
